Hydrogels are crosslinked networks of biological, synthetic, or semi-synthetic polymers. Because hydrogel polymer chains are held together by crosslinks, hydrogels behave like solids rather than liquids, despite the fact that they contain at least 20% water by weight. A significant property of hydrogels is the equilibrium degree of swelling (“Q”), which is the amount of water absorbed by the gel expressed as the ratio of swollen gel volume (or mass) to dry gel volume (or mass). Many hydrogels are responsive to external stimuli in that they expel or absorb water in response to changes in pH, electric field, light intensity, pressure, indirect chemical stimuli, and temperature. The resulting change in hydrogel water content results in a corresponding reversible change in volume.
Hydrogels have many technological uses in both medical and non-medical fields. Owing to their often good biocompatibility and easily adjustable permeability, hydrogels have been used in a range of biomedical applications including contact lenses, diapers, soft and hard tissue prostheses and bioartificial organs.
One of the most interesting potential biomedical applications for hydrogels is the use of these gels as vehicles for the delivery of biologically active solutes. In such an application, the biologically active solute is absorbed into the gel as a solute and thereafter released from the gel over time. The localized delivery of biologically active materials is described, for example, in U.S. Pat. Nos. 5,304,121, 5,674,192 and 5,588,962, and in A. Gutowska et al., “Heparin Release from Thermosensitive Polymer Coatings: In vivo Studies,” 29 J. Biomed. Matls. Res. 811 (1995), each of which is incorporated herein by reference.
Hydrogels are attractive for the delivery of peptide or protein-drugs because they provide a hydrophilic environment for proteins and thus help preserve their activities. Most therapeutic proteins are vulnerable to the proteases in the digestive tract and also have difficulty crossing the skin and other barrier membranes. Implantable drug release systems are thus a viable alternative for delivering therapeutic proteins. Recently, pH-sensitive hydrogels based on poly (N-isopropylacrylamide) (“PNIPA”) have been proposed for enteric drug delivery. In such a system, the gel is collapsed at gastric pH for the negligible release of protein, whereas the gel swells at enteric pH thus permitting sustained release within the intestines.
Hydrogels that undergo reversible volume changes in response to changes in temperature are known as thermosensitive gels. These gels shrink at a transition temperature that is related to the lower critical solution temperature (“LCST”) of the linear polymer from which the gel is made. Specifically, typical thermosensitive gels have an affinity for water and thus swell at temperatures below the transition temperature, whereas they expel water and thus shrink or “deswell” at temperatures above the transition temperature. Thermosensitive hydrogels are potentially of significant utility in biomedical applications, particularly as a means for localized drug delivery. PNIPA is an example of a known thermosensitive hydrogel, as described in R. Dinarvand et al., “The Use of Thermosensitive Hydrogels for On-off Release of Molecules,” 36 J. Controlled Release 221 (1995); A. Gutowska et al., “Thermosensitive Interpenetrating Polymer Networks: Synthesis, Characterization, and Macromolecular Release,” 27 Macromolecules 4167 (1994); R. Yoshida et al., “Drug Release Profiles in the Shrinking Process of Thermoresponsive Poly(N-isopropylacrtlamide-co-alkyl methacrylate) Gels,” 31 Ind. Eng. Chem. Res. 2339 (1992); and Y. Han Bae et al., “Thermo-sensitive Polymers as On-off Switches for Drug Delivery,” 8 Makromol. Chem., Rapid Commun. 481 (1987), each of which is incorporated herein by reference.
Known thermosensitive hydrogels such as PNIPA generally become impermeable to solute when these gels deswell. Consequently, such hydrogels are not applicable to drug delivery systems wherein drug release corresponds to an increase in temperature to above the hydrogel transition temperature. In addition, known thermosensitive hydrogels (e.g., PNIPA) are generally of questionable or uncertain biocompatibility to be safely used in desired drug delivery applications, and as such, FDA approval for the use of PNIPA as part of solute delivery systems remains questionable. Moreover, means for the use of thermosensitive hydrogels in specific localized drug delivery systems have not been detailed in the literature.